Incidence and risk factors for retinopathy of prematurity: a retrospective cohort study

Incidence and risk factors for retinopathy of prematurity: a retrospective cohort study Background and objectives: Advances in neonatal care promoted increased survival rates of preterm infants, with a consequent increase in the number of children affected by retinopathy of prematurity (ROP). This study estimates the incidence of ROP and evaluates potential risk factors associated. Methods: A retrospective cohort study of preterm infants born in a tertiary neonatal intensive care unit was con- ducted from March 2005 to August 2015. Six hundred and thirty-nine newborns were included based on the fol- lowing criteria: infants born with less than 32 weeks’ gestation or birth weight below 1500 g; or neonates born with 32–37 weeks’ gestation or birth weight above 1500 g and any of the following associated: multiple gestation, respira- tory distress syndrome, sepsis, blood transfusions or intraventricular hemorrhage. Neonates were followed up until disease resolution or until treatment criteria was achieved. Results: A total of 602 newborns were evaluated after applying the exclusion criteria. Mean gestational age was 30.7 ± 2.5 weeks. The incidences of ROP at any stage and of type 1 prethreshold ROP were 33.9 and 5.0% respec- tively. Logistic regression analysis revealed that risk factors associated with ROP at any stage were extremely low birth weight (ELBW ) (odds ratio [OR] = 3.10; 95% confidence interval [95% CI]:1.73–5.55), pulmonary diseases (OR = 2.49; 95% CI: 1.35–4.59), intraventricular hemorrhage (OR = 2.17; 95% CI: 1.10–4.30), and low gestational age (OR = 0.81; 95% CI: 0.73–0.91). The main risk factors associated with type 1 prethreshold ROP were pulmonary diseases (OR = 9.58; 95% CI: 1.27–72.04) and ELBW (OR = 3.66; 95% CI: 1.67–8.00). Conclusion: This study found a significant incidence of ROP (33.9%) in the studied population, and highlighted pul- monary diseases as a significant risk factor for type 1 prethreshold ROP. Keywords: Premature birth, Extremely preterm infant, Neonate, Retinopathy of prematurity, Intensive care units, pediatric Background [1–3]. The disease has been extensively studied world - Retinopathy of prematurity (ROP) is a condition char- wide due to increased survival rates among very low birth acterized by the development of abnormal retinal ves- weight preterm newborns (NBs), i.e. with birth weight sels secondary to an incomplete vascularization of the (BW) ≤ 1500  g, who are at the greatest risk for develop- retinal tissue due to hyperoxia causing downregulation ing ROP. These increased numbers may be attributed to of VEGF and death of endothelial cells. This mechanism improved perinatal care. The high rates are leading to a suggests that VEGF plays a vital role for the endothelium. significant raise in the occurrence of other comorbidities Following the closure of growing vessels, the retinal tis- related to preterm birth [4] that have major social reper- sue in development becomes ischemic and hypoxic. This cussion, such as blindness secondary to ROP. Worldwide, process upregulates VEGF leading to neovascularization nearly 10% of all births are premature (before 37  weeks’ gestation) [5]. Blencowe et  al. [6] estimated that every year 32,000 neonates became blind or developed severe *Correspondence: andremfreitas@hotmail.com visual impairment due to ROP worldwide, of which 10% Universidade Federal de Ciências Da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS 90050-170, Brazil were born in Latin American and the Caribbean. The risk Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Freitas et al. Int J Retin Vitr (2018) 4:20 Page 2 of 8 factors associated with ROP were found to vary depend- transfusions, multiple pregnancy, intraventricular ing on the region [7]. These variations are possibly related hemorrhage. to the heterogeneity of the population and discrepancy in neonatal care. Fundoscopy was performed under mydriasis with one ROP is a multifactorial disease [8]. Many studies report drop of 0.5% tropicamide eye drops combined with 1% several risk factors associated with this condition, some phenylephrine eye drops instilled three times in each eye, of which can cause severe ROP (BW, Gestational age with 15-minutes interval in between, before examination. (GA), supplemental oxygen, prolonged mechanical ven- Retinal examination was performed at bedside using tilation, Apgar score, pulmonary complications, ane- a binocular indirect ophthalmoscope (OSF 1.0 Eyetec, mia, intraventricular hemorrhage (IVH), necrotizing São Carlos, Brazil), a 20-diopter lens (Ocular Instru- enterocolitis, sepsis) [2, 9–13]. The identification of risk ments Inc., Bellevue, WA, USA), a newborn eyelid specu- factors interfering with the progression of ROP and the lum (Roca, São Paulo, SP, Brazil), and a pediatric scleral knowledge on its etiology may help ophthalmologists depressor (Roca, São Paulo, SP, Brazil). The examination and neonatologists to perform careful screening, execute was conducted by one of the authors (AMF), an experi- accurate diagnosis, and prevent development of the dis- enced ophthalmologist with competent training in diag- ease. The aim of this study was to estimate the incidence nosis and management of pediatric retinal diseases. of ROP and to assess the association between ROP and Each patient was classified according to the most potential risk factors for this condition, particularly type advanced stage of ROP observed during follow-up assess- 1 prethreshold ROP, in newborns admitted to a neona- ment, considering the eye with more advanced disease, tal intensive care unit (NICU) of a Brazilian tertiary hos- based on the International Classification of Retinopathy pital. Type 1 prethreshold ROP determines the need for of Prematurity [15]. Patients were also classified as pre - treatment. It is defined as zone I any stage ROP with plus senting type 1 prethreshold ROP or not, which deter- disease, or zone I stage 3 ROP without plus disease, or mines the need for treatment, as established by the Early zone II stage 2 or 3 with plus disease [14]. Treatment for Retinopathy of Prematurity (ETROP) ran- domized trial [16]. The first examination was performed between 4 and Patients and methods 6  weeks of chronological age. Subsequent examinations This was a retrospective cohort study of preterm infants were scheduled according to Brazilian ROP Group guide- admitted in a tertiary neonatal intensive care unit from lines, at intervals determined by the findings observed at March 2005 to August 2015. The project was approved by each examination [14]. the Research Ethics Committee of the Federal University Data collection was discontinued when retinal vas- of Health Sciences of Porto Alegre—UFCSPA (Certificate cularization was complete, reaching extreme temporal of Ethical Appreciation no. 45,477,615.4.0000.5335). periphery, or when ROP showed complete regression Inclusion criteria followed the guidelines proposed by after treatment. After that, patients were referred for the Brazilian Council of Ophthalmology and the Brazil- routine follow-up assessment with a pediatric ophthal- ian Society of Pediatric Ophthalmology, presented at the mologist at 6 months of age. Patients discharged from the Workshop of ROP held by the Brazilian ROP Group in NICU were scheduled for outpatient follow-up if reas- 2007 [14]. These guidelines defined the ROP screening sessment was indicated as above. criteria in Brazilian NICUs, and also recommended that Study variables were selected based on the Brazil- NBs with prethreshold type 1 ROP should be treated. ian guidelines for screening and treatment of ROP [14]. Patients who died before complete resolution of ROP We collected data on gender; BW; GA; Apgar scores at 1 or did not attend the outpatient clinic for follow-up and 5 min; number of days on any oxygen therapy or on examinations were excluded from the study. Patients with continuous positive airway pressure (CPAP) or mechani- incomplete data on BW or GA were also excluded, as well cal ventilation; number of blood transfusions; type of as those with congenital glaucoma or congenital cataract. birth (singleton vs. multiple); occurrence of sepsis; use The study included preterm infants meeting one of the of surfactants; occurrence of IVH; use of erythropoietin; following criteria: maternal use of antenatal corticosteroids; and presence of systemic comorbidities such as cardiac diseases (val- (a) BW ≤ 1500 g or GA ≤ 32 weeks; or vulopathy, interatrial or interventricular communication, (b) BW > 1500  g or GA from 32 to 37  weeks and any of patent ductus arteriosus), pulmonary diseases (pneumo- the following risk factors: respiratory distress syn- nia, bronchopulmonary dysplasia, or hyaline membrane drome (hyaline membrane disease), sepsis, blood disease), or digestive diseases (necrotizing enterocolitis or jejunal atresia). Freitas et al. Int J Retin Vitr (2018) 4:20 Page 3 of 8 Statistical calculations were performed using SPSS stage 1 ROP; 26 (4.3%), stage 2 ROP; and 18 (3%), stage 3 software version 22.0, and R software version 3.3.0. ROP. None of the patients developed stages 4 and 5 ROP. Normally distributed quantitative data were expressed Thirty patients (5.0%) developed type 1 prethreshold as mean and standard deviation (SD). Asymmetrically ROP and required treatment. distributed variables were represented as median, mini- In the overall sample, there were 520 neonates with GA mum, and maximum values. Categorical variables were below 32 weeks or with BW below 1500 g, of which 196 reported as counts and percentages. Initially, compari- (37.6%) developed ROP. All 30 patients who developed sons were made between patients with and without ROP. type 1 prethreshold ROP belonged to this subgroup. Subsequently, patients with type 1 prethreshold ROP, i.e., Eight patients with GA above 32  weeks and BW above requiring treatment, were compared with the remain- 1500 g developed ROP, all of those classified as stage 1. ing patients. Quantitative data were analyzed using the Table  1 shows results of bivariate analysis comparing Student’s t test for normally distributed variables or the patients with and without ROP. Statistically significant Mann-Whitney U test for asymmetrically distributed differences were observed between the groups for all var - variables. Categorical data were assessed using the Chi iables, except for gender, type of birth, and presence of square test. A forward stepwise logistic regression model digestive diseases. Multivariate forward stepwise logistic was used to estimate the association between risk factors regression analysis revealed that the risk factors associ- and development of ROP and type 1 prethreshold ROP in ated with the development of ROP at any stage were order to adjust for potential confounding factors. BW < 1000 g, lower GA, occurrence of IVH, and presence In an attempt to minimize bias, a statistical rule of of lung diseases (pneumonia, bronchopulmonary dyspla- thumb suggests that at least 10 cases of the rarest out- sia, or hyaline membrane disease). come event are required per each variable to be included Table  2 shows results of bivariate analysis comparing in a logistic regression model [17]. Since 30 neonates patients with and without type 1 prethreshold ROP. Sta- developed type 1 prethreshold ROP in our study, we tistically significant differences were observed between decided to include three variables in the logistic regres- the groups for all variables, except for gender, type of sion model to evaluate the potential risk factors associ- birth, presence of IVH, use of erythropoietin, maternal ated with this outcome. These variables were selected use of antenatal corticosteroids, and digestive diseases. among the four variables found to be associated with the Among the most relevant variables for the com- development of ROP at any stage, namely BW < 1000  g, parison between groups with ROP and without ROP GA, presence of IVH, and pulmonary comorbidities. Of (BW < 1000  g, occurrence of IVH, and pulmonary dis- these, we decided to exclude GA, because a strong cor- eases), pulmonary diseases and BW < 1000  g remained relation was observed between this variable and BW significant risk factors for type 1 prethreshold ROP after and because GA is a less accurate measure than BW. logistic regression analysis (Table  3). Logistic regression GA is not always an accurate measurement because it analysis revealed that the lower the BW, the higher the is estimated based on the first day of the last menstrual risk for the development of type 1 prethreshold ROP, period, which may be influenced by recall bias, and it is especially in the presence of pulmonary diseases (Fig. 1). also estimated by obstetric ultrasound [18]. Therefore, BW < 1000  g, presence of IVH, and pulmonary comor- Discussion bidities were included in the final logistic regression Table 4 summarizes a comparison between ROP studies. model. Finally, the logistic probability of occurrence of ROP incidence varies considerably, reflecting the differ - type 1 prethreshold ROP was calculated including BW ences in screening criteria, neonatal care and population and pulmonary comorbidities. Statistical significance was heterogeneity. Some risk factors are well stablished (GA, set at P < 0.05. BW), but there is no clear consensus about the others. Many ROP studies screened only infants born with less Results than 32 weeks’ gestation or with less than 1500 g of BW During the study period, 639 patients met the inclusion [4, 11]. In our study, however, we went further and also criteria. Of these, 37 newborns were excluded from the included infants with more than 1500  g or more than study analysis: 25 failed to attend outpatient ophthalmo- 32  weeks’ gestation with determined risk factors associ- logical follow-up visits, 9 died before ROP was resolved, ated. Our results showed that the incidence of ROP at any and 3 had incomplete records. A total of 602 patients stage was 33.9% while the incidence of type 1 prethresh- remained in the study, with mean GA of 30.7 ± 2.5 weeks old ROP was 5.0%. Similarly, in a subgroup analysis of and mean BW of 1274 ± 385  g. Of these, 302 (50.2%) 520 newborns based on the above criteria (infants born were male. A total of 204 patients presented with ROP at less than 32 week’’ gestation or with less than 1500 g), (incidence of 33.9%). Of these, 160 (26.6%) developed 37.6% developed ROP at any stage and 5.7% developed Freitas et al. Int J Retin Vitr (2018) 4:20 Page 4 of 8 Table 1 Risk factors for the development of retinopathy of prematurity (ROP) at any stage Risk factors ROP Without ROP P n = 204 (33.9%) n = 398 (66.1%) Male, n (%) 101 (49.5%) 201 (50.5%) .689 Type of birth, n (%) .832 Singleton 169 (82.8%) 326 (81.9%) Twin or multiple 35 (17.2%) 72 (18.1%) Sepsis, n (%) 167 (83.5%)**** 285 (71.6%) .001 Use of surfactants, n (%) 179 (88.6%)** 258 (65%)* < .001 Intraventricular hemorrhage, n (%) 54 (26.7%)** 50 (12.6%) < .001 Erythropoietin, n (%) 16 (7.9%)** 12 (3%) .006 Maternal use of antenatal corticosteroids, n (%) 58 (28.7%)** 44 (11.1%) < .001 Cardiac diseases, n (%) 69 (33.8%) 51 (12.8%) < .001 Pulmonary diseases, n (%) 171 (83.8%) 250 (62.8%) < .001 Digestive diseases, n (%) 11 (5.4%) 16 (4%) .577 Birth weight < 1000 g, n (%) 98 (48.0%) 50 (12.6%) < .001 Gestational age (weeks), mean ± SD 29.4 (2.5) 31.4 (2.2) < .001 Apgar score at 1 min, mean ± SD 6 (2.3) 6.7 (2.2) .001 Apgar score at 5 min, mean ± SD 7.7 (1.4) 8.2 (1.5) < .001 Days on oxygen therapy, median (minimum to maximum) 27 (0–150) 6 (0–150) < .001 Days on CPAP, median (minimum to maximum) 4 (0–42) 2 (0–30) < .001 Days on mechanical ventilation, median (minimum–maximum) 7 (0–103) 1 (0–150) <.001 Number of blood transfusions, median (minimum to maximum) 1 (0–15) 0 (0–12) < .001 CPAP continuous positive airway pressure *1 newborn with missing data; **2 newborns with missing data; ***3 newborns with missing data; ****4 newborns with missing data chi-square test Student t test Mann-Whitney U test type 1 prethreshold disease. This subgroup included all the risk factors for the development of ROP. Numerous 30 subjects requiring treatment. However, eight patients published case series have shown that infants with ROP in the study who developed stage 1 ROP did not belong in low- and middle-income nations have higher average to this subgroup. The incidences of ROP at any stage BW and GA than infants with ROP in the United States and of type 1 prethreshold ROP in this subgroup were [20]. Most studies report ROP incidences of about 60% at intermediate levels of the range reported in Brazilian for babies with less than 1500  g in nurseries of high- studies that used the same selection criteria. Fortes Filho income countries [21]. In middle-income countries, this et  al. [4] found an incidence of ROP at any stage and of scenario is significantly variable depending on the birth type 1 prethreshold ROP of 29.6 and 7% respectively. conditions and survival rates of premature infants, and Conversely, Gonçalves et  al. [11] found an incidence of due to the fact that ROP occurs in much older and bigger ROP at any stage and of type 1 prethreshold ROP of 44.5 babies than in high-income countries because of varying and 1.8% respectively. The use of various inclusion cri - standards of neonatal care [21]. teria for patients in the screening programs performed The identification of at-risk preterm infants is impor - in different Latin American countries limits any further tant for establishing screening criteria, in order to comparative analysis of the published data. avoid unnecessary ophthalmological examinations and The Vermont Oxford Network database, which collects to ensure the assessment of every premature newborn data from more than 1000 NICUs worldwide, estimated who develops severe ROP. Many studies have been in 2010 an incidence of 33.2% of ROP in neonates with seeking ways of optimizing screening for ROP by con- BW < 1500  g [19]. These variations in the incidence of sidering postnatal weight gain in mathematical mod- ROP may reflect differences in study populations, mor - els to help identify at-risk preterm infants [12, 13, 22]. tality rates, and characteristics of neonatal care in each Some studies have demonstrated that it is possible to institution, corroborating the need to further investigate reduce the number of unnecessary examinations by Freitas et al. Int J Retin Vitr (2018) 4:20 Page 5 of 8 Table 2 Risk factors for the development of retinopathy of prematurity (ROP) with indication for treatment Risk factors With type 1 prethreshold Without type 1 prethreshold P ROP ROP n = 30 (5%) n = 572 (95%) Male, n (%) 12 (40%) 290 (50.7%) .267 Type of birth, n (%) .805 Singleton 24 (80%) 470 (82.5%)** Twin or multiple 6 (20%) 100 (17.5%) Sepsis, n (%) 28 (96.6%)* 424 (74.5%)*** .004 Use of surfactants, n (%) 29 (100%)* 408 (71.6%)** < .001 Intraventricular hemorrhage, n (%) 9 (30%) 95 (16.7%)** .79 Erythropoietin, n (%) 2 (6.7%) 26 (4.6%)** .644 Antenatal corticosteroids, N (%) 8 (27.5%)* 94 (16.5%)* .211 Cardiac diseases, n (%) 12 (40%) 105 (18.4%) .007 Pulmonary diseases, n (%) 29 (96.7%) 392 (68.5%) < .001 Digestive diseases, n (%) 3 (10%) 24 (4.2%) .146 Birth weight < 1000 g, n (%) 18 (60.0%) 130 (22.7%) < .001 Gestational age (weeks), mean ± SD 28.5 (2.6) 31.8 (2.4) < .001 Apgar score at 1 min, mean ± SD 5.6 (2.43) 6.5 (2.2) .006 Apgar score at 5 min, mean ± SD 7.2 (1.6) 8.1 (1.4) < .001 Days on oxygen therapy, median (minimum to maximum) 41 (2–150) 8 (0–150) < .001 Days on CPAP, median (minimum to maximum) 4 (0–42) 2 (0–34) < .001 Days on mechanical ventilation, median (minimum to maximum) 16 (0–60) 2 (0–150) < .001 Number of blood transfusions, median (minimum to maximum) 2 (0–15) 1 (0–14) < .001 CPAP continuous positive airway pressure *1 newborn with missing data; **2 newborns with missing data; ***3 newborns with missing data chi-square test Student t test Mann-Whitney U test Table 3 Risk factors for the development of retinopathy of prematurity (ROP): results of logistic regression analysis Risk factor ROP at any stage n = 204 Type 1 prethreshold ROP n = 30 OR 95% CI P OR 95% CI P Birth weight < 1000 g 3.10 1.73–5.55 < .001 3.66 1.67–8.00 .001 Pulmonary diseases 2.49 1.35–4.59 .004 9.58 1.27–72.04 .028 Intraventricular hemorrhage 2.17 1.10–4.30 .026 1.61 0.69–3.79 .27 Gestational age 0.81 0.73–0.91 .003 OR odds ratio, 95% CI 95% confidence interval using methods with good sensitivity and specificity [22, expanded to NBs with 35  weeks’ gestation in order to 23]. However, these methods have been suggested to identify patients with ROP requiring treatment. assist in selecting and monitoring preterm infants but In our 10-year study, all NBs requiring treatment met not to replace traditional selection criteria for patient the criteria for GA below 32 weeks and BW below 1500 g. screening; hence, they may be validated in other stud- Preterm infants with other risk factors and born with less ies. Looking into this, in 2010 Zin et  al. [23] published than 37 weeks’ gestation were included to ensure a safety a study evaluating methods for selecting NBs to be margin for patient selection, since none of the preterm screened for ROP in seven NICUs in Rio de Janeiro, infants with BW and GA above the previously mentioned southeastern Brazil. Results suggest that, in NICUs values developed ROP requiring treatment. If screening with lower survival rates, selection criteria should be was based strictly on BW and GA, 82 patients (13.6%) Freitas et al. Int J Retin Vitr (2018) 4:20 Page 6 of 8 date, which may be influenced by recall bias, and depends on the availability of obstetric ultrasound. It is also worth mentioning that eight preterm infants born at more than 32  weeks’ gestation and with BW > 1500  g developed stage 1 ROP. Many studies found that the lower the BW and the GA, the greater the risk of developing ROP [2, 4, 9, 24–26]. These findings were corroborated by our logistic regres - sion analysis. Besides these variables, the occurrence of IVH and the presence of pulmonary diseases also remained significant in the logistic regression model. The presence of IVH has been associated with sever - ity of ROP [26, 27]. The development of that condition is related to hypoperfusion and cerebral hypoxia in preterm Fig. 1 Risk for type 1 prethreshold retinopathy of prematurity by a infants and to the rupture of immature subependymal logistic regression model. In patients without pulmonary diseases, progressively lower BW lead to a increase in the risk of developing vessels [27]. Therefore, IVH and ROP are both charac - type 1 prethreshold ROP, however, in lower percentage when terized by tissue ischemia and vascular immaturity. Our compared to the group with pulmonary diseases results corroborate the recommendation of Brazilian guidelines for screening and treatment of ROP, which point out IVH as an important risk factor to be consid- would not undergo examination. However, it is important ered in the selection of patients to be assessed [14]. to note that GA is not always an accurate measurement, The presence of pulmonary diseases was an important because it is estimated based on the last menstruation risk factor for the development of both ROP at any stage Table 4 Studies on the incidence and risk factors for ROP Author Country Year Study design Patients (n) Inclusion criteria Incidence Main risk factors of publication of any stage ROP (%) Schaffer et al. (CRYO- United States 1993 MRCT 4099 BW < 1251 g 66.0 GA, BW, multiple ROP Study) [31] births, Out of nurs- ery birth, white race Good et al. (ET-ROP United States 2004 MRCT 6998 BW < 1251 g 68.0 NR Study) [16] Fortes Filho et al. [4] Brazil 2009 PCS 450 BW < 1500 g or 24.2 GA, BW, PMV, sepsis, GA < 32 w IVH, BT Zin et al. [23] Brazil 2010 PCS 3437 BW < 2000 g or GA < 19.9 NR 37 w Lomuto et al. [32] Argentina 2010 RCS 956 BW < 1500 g or 26.2 NR GA < 32 w Gonçalves et al. [11] Brazil 2014 PCS 110 BW < 1500 g or 44.5 GA, BW, BT, sepsis GA < 32 w Mitsiakos et al. [33] Canada 2016 RCS 1562 GA < 32 w 15.6 BW, sepsis, NEC, PDA, PMV Yau et al. [34] China 2016 RCS 513 BW < 1500 g or 18.5 GA, BW, IVH GA < 32 w Owen et al. [35] United States 2017 RCS 457 BW < 1250 g or 47.5 GA, BW, maternal Mg GA < 30 w prophylaxis, need of any surgery Ahuja et al. [36] India 2018 PCS 325 BW < 1900, GA < 32.6 BW 36 w Bas et al. [37] Turkey 2018 PCS 6115 BW < 1500 g, or 27.0 GA, BW, days on GA < 32 w, or oxygen, sepsis, BT, unstable clinical relative weight gain course ROP retinopathy of prematurity, MRCT multicenter randomized clinical trial, PCS prospective cohort study, RCS retrospective cohort study, g grams, w weeks, NR not reported, GA gestational age, BW birth weight, PMV prolongued mechanical ventilation, IVH intraventricular hemorrhage, BT blood transfusions, NEC necrotizing enterocolitis; PDA persistent ductus arteriosus, Mg magnesium Freitas et al. Int J Retin Vitr (2018) 4:20 Page 7 of 8 and type 1 prethreshold ROP. This observation suggests BW, low GA, and IVH. Our results revealed that impaired that pulmonary diseases may be used as markers for the lung function as shown by the occurrence of pneumonia, need of larger amount of supplemental oxygen, which is hyaline membrane disease, or bronchopulmonary dys- known to be essential in the pathogenesis of ROP [28]. In plasia, is an important risk factor for the development addition, pulmonary diseases are also possibly associated of ROP and a determinant element of increased risk of with fluctuations in oxygen concentration and episodes of developing type 1 prethreshold ROP. This stage of ROP intermittent hypoxia that are also related to a greater risk of maintains the greatest interest, because it establishes developing ROP [29]. the need of therapeutic intervention. To the best of our The logistic regression model revealed that pulmonary knowledge, this is the first study reporting the associa - diseases and BW < 1000 g are the main risk factors for the tion between pulmonary diseases and type 1 prethresh- development of type 1 prethreshold ROP. BW as a continu- old ROP. Further prospective studies assessing these ous variable and the presence of pulmonary diseases were variables are required in order to evaluate the magnitude used to calculate the logistic probability of development of of the cause-effect relationship between pulmonary dis - type 1 prethreshold ROP. Figure 1 shows that the lower the eases and severe ROP. BW, the greater the probability of type 1 prethreshold ROP. This figure also illustrates that the association between low Abbreviations BW and pulmonary diseases is a determining factor in the ROP: retinopathy of prematurity; BW: birth weight; CPAP: continuous positive increase of this probability. This figure demonstrates that, airway pressure; ELBW: extremely low birth weight; ETROP: early treatment for retinopathy of prematurity; GA: gestational age; IVH: intraventricular hemor- in patients without pulmonary diseases, progressively rhage; NB: newborn; NICU: neonatal intensive care unit. lower BW lead to an increase in the risk of developing type 1 prethreshold ROP, however, in lower percentage when Authors’ contributions AMF conceptualized and designed the study, collected data, designed the compared to the group with pulmonary diseases. database, carried out the statistical analyses and interpretation, drafted the The aim of this study was not to assess the outcome of initial manuscript, and critically reviewed and revised the manuscript. RM patients with type 1 prethreshold disease, but it is worth and ELR supervised the study and critically reviewed the manuscript. MRT collected data and critically reviewed and revised the manuscript. All authors mentioning that they were all treated with diode laser pho- read and approved the final manuscript. tocoagulation and showed complete regression of ROP. The limitations of the present study include its retrospec - Author details Universidade Federal de Ciências Da Saúde de Porto Alegre (UFCSPA), Rua tive nature limiting the control over the quality of meas- Sarmento Leite, 245, Porto Alegre, RS 90050-170, Brazil. Royal Liverpool urements. It should also be taken into account that we University Hospital, Prescot St, Liverpool L7 8XP, UK. have included neonates born over a 10-year period, when Acknowledgements changes in neonatal care may have been implemented. We would like to thank Paulo Henrique Englert, MD; Luciana Emilia Reginato, Nevertheless, the advantages of the study, which ensured MD; Betina Wächter, MD; Debora Cestari, MD. its clinical importance, include a robust sample size, the Competing interests assessment of the disease under study by a single trained The authors declare that they have no competing interests. examiner, and the availability of intensive care resources at a tertiary hospital serving a large population of a metro- Availability of data and materials The datasets used and/or analysed during the current study are available from politan area. Furthermore, a detailed statistical analysis was the corresponding author on reasonable request. determinant to reduce study bias. Although a variety of instruments have been available to Consent for publication Not applicable. image premature neonates, we did not have access to imag- ing devices during the course of the study. Objective docu- Ethics approval and consent to participate mentation of the disease requires a trained imager with The project was approved by the Research Ethics Committee of Santa Casa de Misericórdia de Porto Alegre (Certificate of Ethical Appreciation no. skills to obtain images of satisfactory quality. Expert grad- 45,477,615.4.0000.5335). The ethics committee does not require informed con- ing is accurate and used to compare with imaging graders sent from patients in retrospective cohort studies. The authors have signed a in several studies [30]. confidentiality agreement regarding collected data. Funding Conclusion The authors have no financial relationships relevant to this article to disclose. Although the incidence of ROP in our study was at inter- mediate levels compared to Brazilian studies with anal- Publisher’s Note ogous design, our mean incidence was very similar to Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. worldwide results, as the Vermont Oxford Network data- base. Our study contributed to the analysis of risk factors Received: 5 March 2018 Accepted: 26 May 2018 associated with ROP, supporting the importance of low Freitas et al. Int J Retin Vitr (2018) 4:20 Page 8 of 8 References 20. Kim SJ, Port AD, Swan R, Campbell JP, Chan RVP, Chiang MF. Retinopathy 1. Beharry KD, Valencia GB, Lazzaro DR, Aranda JV. Pharmacologic interven- of prematurity: a review of risk factors and their clinical significance. Surv tions for the prevention and treatment of retinopathy of prematurity. Ophthalmol. 2018. https ://doi.org/10.1016/j.survo phtha l.2018.04.002. Semin Perinatol. 2016;40:189–202. 21. 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Pediatr Res. 2013;74(Suppl 1):35–49. severe neonatal morbidities on long term outcome in extremely low 7. Carrion JZ, Fortes Filho JB, Tartarella MB, Zin A, Jornada ID Jr. Preva- birthweight infants. Korean J Pediatr. 2010;53:694–700. lence of retinopathy of prematurity in Latin America. Clin Ophthalmol. 27. Watts P, Adams GG, Thomas RM, Bunce C. Intraventricular haemorrhage 2011;5:1687–95. and stage 3 retinopathy of prematurity. Br J Ophthalmol. 2000;84:596–9. 8. Smith LE. Pathogenesis of retinopathy of prematurity. Semin Neonatol. 28. Saugstad OD, Aune D. Optimal oxygenation of extremely low birth 2003;8:469–73. weight infants: a meta-analysis and systematic review of the oxygen 9. Darlow BA, Hutchinson JL, Henderson-Smart DJ, Donoghue DA, Simpson saturation target studies. Neonatology. 2014;105:55–63. JM, Evans NJ. Prenatal risk factors for severe retinopathy of prematurity 29. Di Fiore JM, Bloom JN, Orge F, Schutt A, Schluchter M, Cheruvu VK, et al. 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Incidence and risk factors for retinopathy of prematurity in a Brazil- cryotherapy for retinopathy of prematurity cooperative group. Ophthal- ian reference service. Sao Paulo Med J. 2014;132:85–91. mology. 1993;100(2):230–7. 12. Binenbaum G. Algorithms for the prediction of retinopathy of prematu- 32. Lomuto CC, Galina L, Brussa M, Quiroga A, Alda E, Benitez AM, Bouzas L, rity based on postnatal weight gain. Clin Perinatol. 2013;40:261–70. Dinerstein NA, Erpen N, Falbo J, Manzitti J, Marinaro S, Nieto R, Sepulveda 13. Eckert GU, Fortes Filho JB, Maia M, Procianoy RS. A predictive score for T, Visintin P. Epidemiology of retinopathy of prematurity in public services retinopathy of prematurity in very low birth weight preterm infants. Eye from Argentina during 2008. Arch Argent Pediatr. 2010;108(1):24–30. (Lond). 2012;26:400–6. 33. Mitsiakos G, Papageorgiou A. Incidence and factors predisposing to retin- 14. Zin A, Florêncio T, Fortes Filho JB, Nakanami CR, Gianini N, Graziano opathy of prematurity in inborn infants less than 32 weeks of gestation. RM, et al. Proposta de diretrizes brasileiras do exame e tratamento de Hippokratia. 2016;20(2):121–6. retinopatia da prematuridade (ROP). Arquivos Brasileiros de Oftalmologia. 34. Yau GS, Lee JW, Tam VT, Liu CC, Yip S, Cheng E, Chu BC, Yuen CY. Incidence 2007;70:875–83. and risk factors of retinopathy of prematurity from 2 neonatal intensive 15. Gole GA, et al. The international classification of retinopathy of prematu- care units in a Hong Kong Chinese population. Asia Pac J Ophthalmol rity revisited. Arch Ophthalmol. 2005;123:991–9. (Phila). 2016;5(3):185–91. 16. Good WV. Final results of the Early Treatment for Retinopathy of Prematu- 35. Owen LA, Morrison MA, Hoffman RO, Yoder BA, DeAngelis MM. Retin- rity (ETROP) randomized trial. Trans Am Ophthalmol Soc. 2004;102:233– opathy of prematurity: a comprehensive risk analysis for prevention and 48 (discussion 48-50). prediction of disease. PLoS ONE. 2017;12(2):1–14. 17. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation 36. Ahuja AA, Reddy YC, Adenuga OO, Kewlani D, Ravindran M, Ramakrishnan study of the number of events per variable in logistic regression analysis. R. Risk factors for retinopathy of prematurity in a district in South India: a J Clin Epidemiol. 1996;49:1373–9. prospective cohort study. Oman J Ophthalmol. 2018;11(1):33–7. 18. Committee on Obstetric Practice, the American Institute of Ultrasound 37. Bas AY, Demirel N, Koc E, Ulubas Isik D, Hirfanoglu İM, Tunc T. Incidence, in Medicine, and the Society for Maternal-Fetal Medicine. Committee risk factors and severity of retinopathy of prematurity in Turkey ( TR-ROP Opinion No 700: Methods for Estimating the Due Date. Obstet Gynecol. study): a prospective, multicentre study in 69 neonatal intensive care 2017 May;129(5):e150-e154. units. Br J Ophthalmol [Internet]. 2018;bjophthalmol-2017-311789. Avail- 19. Cavallaro G, Filippi L, Bagnoli P, La Marca G, Cristofori G, Raffaeli G, et al. able from: http://bjo.bmj.com/looku p/doi/10.1136/bjoph thalm ol-2017- The pathophysiology of retinopathy of prematurity: an update of previ-31178 9. ous and recent knowledge. Acta Ophthalmol. 2014;92:2–20. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Retina and Vitreous Springer Journals

Incidence and risk factors for retinopathy of prematurity: a retrospective cohort study

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Abstract

Background and objectives: Advances in neonatal care promoted increased survival rates of preterm infants, with a consequent increase in the number of children affected by retinopathy of prematurity (ROP). This study estimates the incidence of ROP and evaluates potential risk factors associated. Methods: A retrospective cohort study of preterm infants born in a tertiary neonatal intensive care unit was con- ducted from March 2005 to August 2015. Six hundred and thirty-nine newborns were included based on the fol- lowing criteria: infants born with less than 32 weeks’ gestation or birth weight below 1500 g; or neonates born with 32–37 weeks’ gestation or birth weight above 1500 g and any of the following associated: multiple gestation, respira- tory distress syndrome, sepsis, blood transfusions or intraventricular hemorrhage. Neonates were followed up until disease resolution or until treatment criteria was achieved. Results: A total of 602 newborns were evaluated after applying the exclusion criteria. Mean gestational age was 30.7 ± 2.5 weeks. The incidences of ROP at any stage and of type 1 prethreshold ROP were 33.9 and 5.0% respec- tively. Logistic regression analysis revealed that risk factors associated with ROP at any stage were extremely low birth weight (ELBW ) (odds ratio [OR] = 3.10; 95% confidence interval [95% CI]:1.73–5.55), pulmonary diseases (OR = 2.49; 95% CI: 1.35–4.59), intraventricular hemorrhage (OR = 2.17; 95% CI: 1.10–4.30), and low gestational age (OR = 0.81; 95% CI: 0.73–0.91). The main risk factors associated with type 1 prethreshold ROP were pulmonary diseases (OR = 9.58; 95% CI: 1.27–72.04) and ELBW (OR = 3.66; 95% CI: 1.67–8.00). Conclusion: This study found a significant incidence of ROP (33.9%) in the studied population, and highlighted pul- monary diseases as a significant risk factor for type 1 prethreshold ROP. Keywords: Premature birth, Extremely preterm infant, Neonate, Retinopathy of prematurity, Intensive care units, pediatric Background [1–3]. The disease has been extensively studied world - Retinopathy of prematurity (ROP) is a condition char- wide due to increased survival rates among very low birth acterized by the development of abnormal retinal ves- weight preterm newborns (NBs), i.e. with birth weight sels secondary to an incomplete vascularization of the (BW) ≤ 1500  g, who are at the greatest risk for develop- retinal tissue due to hyperoxia causing downregulation ing ROP. These increased numbers may be attributed to of VEGF and death of endothelial cells. This mechanism improved perinatal care. The high rates are leading to a suggests that VEGF plays a vital role for the endothelium. significant raise in the occurrence of other comorbidities Following the closure of growing vessels, the retinal tis- related to preterm birth [4] that have major social reper- sue in development becomes ischemic and hypoxic. This cussion, such as blindness secondary to ROP. Worldwide, process upregulates VEGF leading to neovascularization nearly 10% of all births are premature (before 37  weeks’ gestation) [5]. Blencowe et  al. [6] estimated that every year 32,000 neonates became blind or developed severe *Correspondence: andremfreitas@hotmail.com visual impairment due to ROP worldwide, of which 10% Universidade Federal de Ciências Da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS 90050-170, Brazil were born in Latin American and the Caribbean. The risk Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Freitas et al. Int J Retin Vitr (2018) 4:20 Page 2 of 8 factors associated with ROP were found to vary depend- transfusions, multiple pregnancy, intraventricular ing on the region [7]. These variations are possibly related hemorrhage. to the heterogeneity of the population and discrepancy in neonatal care. Fundoscopy was performed under mydriasis with one ROP is a multifactorial disease [8]. Many studies report drop of 0.5% tropicamide eye drops combined with 1% several risk factors associated with this condition, some phenylephrine eye drops instilled three times in each eye, of which can cause severe ROP (BW, Gestational age with 15-minutes interval in between, before examination. (GA), supplemental oxygen, prolonged mechanical ven- Retinal examination was performed at bedside using tilation, Apgar score, pulmonary complications, ane- a binocular indirect ophthalmoscope (OSF 1.0 Eyetec, mia, intraventricular hemorrhage (IVH), necrotizing São Carlos, Brazil), a 20-diopter lens (Ocular Instru- enterocolitis, sepsis) [2, 9–13]. The identification of risk ments Inc., Bellevue, WA, USA), a newborn eyelid specu- factors interfering with the progression of ROP and the lum (Roca, São Paulo, SP, Brazil), and a pediatric scleral knowledge on its etiology may help ophthalmologists depressor (Roca, São Paulo, SP, Brazil). The examination and neonatologists to perform careful screening, execute was conducted by one of the authors (AMF), an experi- accurate diagnosis, and prevent development of the dis- enced ophthalmologist with competent training in diag- ease. The aim of this study was to estimate the incidence nosis and management of pediatric retinal diseases. of ROP and to assess the association between ROP and Each patient was classified according to the most potential risk factors for this condition, particularly type advanced stage of ROP observed during follow-up assess- 1 prethreshold ROP, in newborns admitted to a neona- ment, considering the eye with more advanced disease, tal intensive care unit (NICU) of a Brazilian tertiary hos- based on the International Classification of Retinopathy pital. Type 1 prethreshold ROP determines the need for of Prematurity [15]. Patients were also classified as pre - treatment. It is defined as zone I any stage ROP with plus senting type 1 prethreshold ROP or not, which deter- disease, or zone I stage 3 ROP without plus disease, or mines the need for treatment, as established by the Early zone II stage 2 or 3 with plus disease [14]. Treatment for Retinopathy of Prematurity (ETROP) ran- domized trial [16]. The first examination was performed between 4 and Patients and methods 6  weeks of chronological age. Subsequent examinations This was a retrospective cohort study of preterm infants were scheduled according to Brazilian ROP Group guide- admitted in a tertiary neonatal intensive care unit from lines, at intervals determined by the findings observed at March 2005 to August 2015. The project was approved by each examination [14]. the Research Ethics Committee of the Federal University Data collection was discontinued when retinal vas- of Health Sciences of Porto Alegre—UFCSPA (Certificate cularization was complete, reaching extreme temporal of Ethical Appreciation no. 45,477,615.4.0000.5335). periphery, or when ROP showed complete regression Inclusion criteria followed the guidelines proposed by after treatment. After that, patients were referred for the Brazilian Council of Ophthalmology and the Brazil- routine follow-up assessment with a pediatric ophthal- ian Society of Pediatric Ophthalmology, presented at the mologist at 6 months of age. Patients discharged from the Workshop of ROP held by the Brazilian ROP Group in NICU were scheduled for outpatient follow-up if reas- 2007 [14]. These guidelines defined the ROP screening sessment was indicated as above. criteria in Brazilian NICUs, and also recommended that Study variables were selected based on the Brazil- NBs with prethreshold type 1 ROP should be treated. ian guidelines for screening and treatment of ROP [14]. Patients who died before complete resolution of ROP We collected data on gender; BW; GA; Apgar scores at 1 or did not attend the outpatient clinic for follow-up and 5 min; number of days on any oxygen therapy or on examinations were excluded from the study. Patients with continuous positive airway pressure (CPAP) or mechani- incomplete data on BW or GA were also excluded, as well cal ventilation; number of blood transfusions; type of as those with congenital glaucoma or congenital cataract. birth (singleton vs. multiple); occurrence of sepsis; use The study included preterm infants meeting one of the of surfactants; occurrence of IVH; use of erythropoietin; following criteria: maternal use of antenatal corticosteroids; and presence of systemic comorbidities such as cardiac diseases (val- (a) BW ≤ 1500 g or GA ≤ 32 weeks; or vulopathy, interatrial or interventricular communication, (b) BW > 1500  g or GA from 32 to 37  weeks and any of patent ductus arteriosus), pulmonary diseases (pneumo- the following risk factors: respiratory distress syn- nia, bronchopulmonary dysplasia, or hyaline membrane drome (hyaline membrane disease), sepsis, blood disease), or digestive diseases (necrotizing enterocolitis or jejunal atresia). Freitas et al. Int J Retin Vitr (2018) 4:20 Page 3 of 8 Statistical calculations were performed using SPSS stage 1 ROP; 26 (4.3%), stage 2 ROP; and 18 (3%), stage 3 software version 22.0, and R software version 3.3.0. ROP. None of the patients developed stages 4 and 5 ROP. Normally distributed quantitative data were expressed Thirty patients (5.0%) developed type 1 prethreshold as mean and standard deviation (SD). Asymmetrically ROP and required treatment. distributed variables were represented as median, mini- In the overall sample, there were 520 neonates with GA mum, and maximum values. Categorical variables were below 32 weeks or with BW below 1500 g, of which 196 reported as counts and percentages. Initially, compari- (37.6%) developed ROP. All 30 patients who developed sons were made between patients with and without ROP. type 1 prethreshold ROP belonged to this subgroup. Subsequently, patients with type 1 prethreshold ROP, i.e., Eight patients with GA above 32  weeks and BW above requiring treatment, were compared with the remain- 1500 g developed ROP, all of those classified as stage 1. ing patients. Quantitative data were analyzed using the Table  1 shows results of bivariate analysis comparing Student’s t test for normally distributed variables or the patients with and without ROP. Statistically significant Mann-Whitney U test for asymmetrically distributed differences were observed between the groups for all var - variables. Categorical data were assessed using the Chi iables, except for gender, type of birth, and presence of square test. A forward stepwise logistic regression model digestive diseases. Multivariate forward stepwise logistic was used to estimate the association between risk factors regression analysis revealed that the risk factors associ- and development of ROP and type 1 prethreshold ROP in ated with the development of ROP at any stage were order to adjust for potential confounding factors. BW < 1000 g, lower GA, occurrence of IVH, and presence In an attempt to minimize bias, a statistical rule of of lung diseases (pneumonia, bronchopulmonary dyspla- thumb suggests that at least 10 cases of the rarest out- sia, or hyaline membrane disease). come event are required per each variable to be included Table  2 shows results of bivariate analysis comparing in a logistic regression model [17]. Since 30 neonates patients with and without type 1 prethreshold ROP. Sta- developed type 1 prethreshold ROP in our study, we tistically significant differences were observed between decided to include three variables in the logistic regres- the groups for all variables, except for gender, type of sion model to evaluate the potential risk factors associ- birth, presence of IVH, use of erythropoietin, maternal ated with this outcome. These variables were selected use of antenatal corticosteroids, and digestive diseases. among the four variables found to be associated with the Among the most relevant variables for the com- development of ROP at any stage, namely BW < 1000  g, parison between groups with ROP and without ROP GA, presence of IVH, and pulmonary comorbidities. Of (BW < 1000  g, occurrence of IVH, and pulmonary dis- these, we decided to exclude GA, because a strong cor- eases), pulmonary diseases and BW < 1000  g remained relation was observed between this variable and BW significant risk factors for type 1 prethreshold ROP after and because GA is a less accurate measure than BW. logistic regression analysis (Table  3). Logistic regression GA is not always an accurate measurement because it analysis revealed that the lower the BW, the higher the is estimated based on the first day of the last menstrual risk for the development of type 1 prethreshold ROP, period, which may be influenced by recall bias, and it is especially in the presence of pulmonary diseases (Fig. 1). also estimated by obstetric ultrasound [18]. Therefore, BW < 1000  g, presence of IVH, and pulmonary comor- Discussion bidities were included in the final logistic regression Table 4 summarizes a comparison between ROP studies. model. Finally, the logistic probability of occurrence of ROP incidence varies considerably, reflecting the differ - type 1 prethreshold ROP was calculated including BW ences in screening criteria, neonatal care and population and pulmonary comorbidities. Statistical significance was heterogeneity. Some risk factors are well stablished (GA, set at P < 0.05. BW), but there is no clear consensus about the others. Many ROP studies screened only infants born with less Results than 32 weeks’ gestation or with less than 1500 g of BW During the study period, 639 patients met the inclusion [4, 11]. In our study, however, we went further and also criteria. Of these, 37 newborns were excluded from the included infants with more than 1500  g or more than study analysis: 25 failed to attend outpatient ophthalmo- 32  weeks’ gestation with determined risk factors associ- logical follow-up visits, 9 died before ROP was resolved, ated. Our results showed that the incidence of ROP at any and 3 had incomplete records. A total of 602 patients stage was 33.9% while the incidence of type 1 prethresh- remained in the study, with mean GA of 30.7 ± 2.5 weeks old ROP was 5.0%. Similarly, in a subgroup analysis of and mean BW of 1274 ± 385  g. Of these, 302 (50.2%) 520 newborns based on the above criteria (infants born were male. A total of 204 patients presented with ROP at less than 32 week’’ gestation or with less than 1500 g), (incidence of 33.9%). Of these, 160 (26.6%) developed 37.6% developed ROP at any stage and 5.7% developed Freitas et al. Int J Retin Vitr (2018) 4:20 Page 4 of 8 Table 1 Risk factors for the development of retinopathy of prematurity (ROP) at any stage Risk factors ROP Without ROP P n = 204 (33.9%) n = 398 (66.1%) Male, n (%) 101 (49.5%) 201 (50.5%) .689 Type of birth, n (%) .832 Singleton 169 (82.8%) 326 (81.9%) Twin or multiple 35 (17.2%) 72 (18.1%) Sepsis, n (%) 167 (83.5%)**** 285 (71.6%) .001 Use of surfactants, n (%) 179 (88.6%)** 258 (65%)* < .001 Intraventricular hemorrhage, n (%) 54 (26.7%)** 50 (12.6%) < .001 Erythropoietin, n (%) 16 (7.9%)** 12 (3%) .006 Maternal use of antenatal corticosteroids, n (%) 58 (28.7%)** 44 (11.1%) < .001 Cardiac diseases, n (%) 69 (33.8%) 51 (12.8%) < .001 Pulmonary diseases, n (%) 171 (83.8%) 250 (62.8%) < .001 Digestive diseases, n (%) 11 (5.4%) 16 (4%) .577 Birth weight < 1000 g, n (%) 98 (48.0%) 50 (12.6%) < .001 Gestational age (weeks), mean ± SD 29.4 (2.5) 31.4 (2.2) < .001 Apgar score at 1 min, mean ± SD 6 (2.3) 6.7 (2.2) .001 Apgar score at 5 min, mean ± SD 7.7 (1.4) 8.2 (1.5) < .001 Days on oxygen therapy, median (minimum to maximum) 27 (0–150) 6 (0–150) < .001 Days on CPAP, median (minimum to maximum) 4 (0–42) 2 (0–30) < .001 Days on mechanical ventilation, median (minimum–maximum) 7 (0–103) 1 (0–150) <.001 Number of blood transfusions, median (minimum to maximum) 1 (0–15) 0 (0–12) < .001 CPAP continuous positive airway pressure *1 newborn with missing data; **2 newborns with missing data; ***3 newborns with missing data; ****4 newborns with missing data chi-square test Student t test Mann-Whitney U test type 1 prethreshold disease. This subgroup included all the risk factors for the development of ROP. Numerous 30 subjects requiring treatment. However, eight patients published case series have shown that infants with ROP in the study who developed stage 1 ROP did not belong in low- and middle-income nations have higher average to this subgroup. The incidences of ROP at any stage BW and GA than infants with ROP in the United States and of type 1 prethreshold ROP in this subgroup were [20]. Most studies report ROP incidences of about 60% at intermediate levels of the range reported in Brazilian for babies with less than 1500  g in nurseries of high- studies that used the same selection criteria. Fortes Filho income countries [21]. In middle-income countries, this et  al. [4] found an incidence of ROP at any stage and of scenario is significantly variable depending on the birth type 1 prethreshold ROP of 29.6 and 7% respectively. conditions and survival rates of premature infants, and Conversely, Gonçalves et  al. [11] found an incidence of due to the fact that ROP occurs in much older and bigger ROP at any stage and of type 1 prethreshold ROP of 44.5 babies than in high-income countries because of varying and 1.8% respectively. The use of various inclusion cri - standards of neonatal care [21]. teria for patients in the screening programs performed The identification of at-risk preterm infants is impor - in different Latin American countries limits any further tant for establishing screening criteria, in order to comparative analysis of the published data. avoid unnecessary ophthalmological examinations and The Vermont Oxford Network database, which collects to ensure the assessment of every premature newborn data from more than 1000 NICUs worldwide, estimated who develops severe ROP. Many studies have been in 2010 an incidence of 33.2% of ROP in neonates with seeking ways of optimizing screening for ROP by con- BW < 1500  g [19]. These variations in the incidence of sidering postnatal weight gain in mathematical mod- ROP may reflect differences in study populations, mor - els to help identify at-risk preterm infants [12, 13, 22]. tality rates, and characteristics of neonatal care in each Some studies have demonstrated that it is possible to institution, corroborating the need to further investigate reduce the number of unnecessary examinations by Freitas et al. Int J Retin Vitr (2018) 4:20 Page 5 of 8 Table 2 Risk factors for the development of retinopathy of prematurity (ROP) with indication for treatment Risk factors With type 1 prethreshold Without type 1 prethreshold P ROP ROP n = 30 (5%) n = 572 (95%) Male, n (%) 12 (40%) 290 (50.7%) .267 Type of birth, n (%) .805 Singleton 24 (80%) 470 (82.5%)** Twin or multiple 6 (20%) 100 (17.5%) Sepsis, n (%) 28 (96.6%)* 424 (74.5%)*** .004 Use of surfactants, n (%) 29 (100%)* 408 (71.6%)** < .001 Intraventricular hemorrhage, n (%) 9 (30%) 95 (16.7%)** .79 Erythropoietin, n (%) 2 (6.7%) 26 (4.6%)** .644 Antenatal corticosteroids, N (%) 8 (27.5%)* 94 (16.5%)* .211 Cardiac diseases, n (%) 12 (40%) 105 (18.4%) .007 Pulmonary diseases, n (%) 29 (96.7%) 392 (68.5%) < .001 Digestive diseases, n (%) 3 (10%) 24 (4.2%) .146 Birth weight < 1000 g, n (%) 18 (60.0%) 130 (22.7%) < .001 Gestational age (weeks), mean ± SD 28.5 (2.6) 31.8 (2.4) < .001 Apgar score at 1 min, mean ± SD 5.6 (2.43) 6.5 (2.2) .006 Apgar score at 5 min, mean ± SD 7.2 (1.6) 8.1 (1.4) < .001 Days on oxygen therapy, median (minimum to maximum) 41 (2–150) 8 (0–150) < .001 Days on CPAP, median (minimum to maximum) 4 (0–42) 2 (0–34) < .001 Days on mechanical ventilation, median (minimum to maximum) 16 (0–60) 2 (0–150) < .001 Number of blood transfusions, median (minimum to maximum) 2 (0–15) 1 (0–14) < .001 CPAP continuous positive airway pressure *1 newborn with missing data; **2 newborns with missing data; ***3 newborns with missing data chi-square test Student t test Mann-Whitney U test Table 3 Risk factors for the development of retinopathy of prematurity (ROP): results of logistic regression analysis Risk factor ROP at any stage n = 204 Type 1 prethreshold ROP n = 30 OR 95% CI P OR 95% CI P Birth weight < 1000 g 3.10 1.73–5.55 < .001 3.66 1.67–8.00 .001 Pulmonary diseases 2.49 1.35–4.59 .004 9.58 1.27–72.04 .028 Intraventricular hemorrhage 2.17 1.10–4.30 .026 1.61 0.69–3.79 .27 Gestational age 0.81 0.73–0.91 .003 OR odds ratio, 95% CI 95% confidence interval using methods with good sensitivity and specificity [22, expanded to NBs with 35  weeks’ gestation in order to 23]. However, these methods have been suggested to identify patients with ROP requiring treatment. assist in selecting and monitoring preterm infants but In our 10-year study, all NBs requiring treatment met not to replace traditional selection criteria for patient the criteria for GA below 32 weeks and BW below 1500 g. screening; hence, they may be validated in other stud- Preterm infants with other risk factors and born with less ies. Looking into this, in 2010 Zin et  al. [23] published than 37 weeks’ gestation were included to ensure a safety a study evaluating methods for selecting NBs to be margin for patient selection, since none of the preterm screened for ROP in seven NICUs in Rio de Janeiro, infants with BW and GA above the previously mentioned southeastern Brazil. Results suggest that, in NICUs values developed ROP requiring treatment. If screening with lower survival rates, selection criteria should be was based strictly on BW and GA, 82 patients (13.6%) Freitas et al. Int J Retin Vitr (2018) 4:20 Page 6 of 8 date, which may be influenced by recall bias, and depends on the availability of obstetric ultrasound. It is also worth mentioning that eight preterm infants born at more than 32  weeks’ gestation and with BW > 1500  g developed stage 1 ROP. Many studies found that the lower the BW and the GA, the greater the risk of developing ROP [2, 4, 9, 24–26]. These findings were corroborated by our logistic regres - sion analysis. Besides these variables, the occurrence of IVH and the presence of pulmonary diseases also remained significant in the logistic regression model. The presence of IVH has been associated with sever - ity of ROP [26, 27]. The development of that condition is related to hypoperfusion and cerebral hypoxia in preterm Fig. 1 Risk for type 1 prethreshold retinopathy of prematurity by a infants and to the rupture of immature subependymal logistic regression model. In patients without pulmonary diseases, progressively lower BW lead to a increase in the risk of developing vessels [27]. Therefore, IVH and ROP are both charac - type 1 prethreshold ROP, however, in lower percentage when terized by tissue ischemia and vascular immaturity. Our compared to the group with pulmonary diseases results corroborate the recommendation of Brazilian guidelines for screening and treatment of ROP, which point out IVH as an important risk factor to be consid- would not undergo examination. However, it is important ered in the selection of patients to be assessed [14]. to note that GA is not always an accurate measurement, The presence of pulmonary diseases was an important because it is estimated based on the last menstruation risk factor for the development of both ROP at any stage Table 4 Studies on the incidence and risk factors for ROP Author Country Year Study design Patients (n) Inclusion criteria Incidence Main risk factors of publication of any stage ROP (%) Schaffer et al. (CRYO- United States 1993 MRCT 4099 BW < 1251 g 66.0 GA, BW, multiple ROP Study) [31] births, Out of nurs- ery birth, white race Good et al. (ET-ROP United States 2004 MRCT 6998 BW < 1251 g 68.0 NR Study) [16] Fortes Filho et al. [4] Brazil 2009 PCS 450 BW < 1500 g or 24.2 GA, BW, PMV, sepsis, GA < 32 w IVH, BT Zin et al. [23] Brazil 2010 PCS 3437 BW < 2000 g or GA < 19.9 NR 37 w Lomuto et al. [32] Argentina 2010 RCS 956 BW < 1500 g or 26.2 NR GA < 32 w Gonçalves et al. [11] Brazil 2014 PCS 110 BW < 1500 g or 44.5 GA, BW, BT, sepsis GA < 32 w Mitsiakos et al. [33] Canada 2016 RCS 1562 GA < 32 w 15.6 BW, sepsis, NEC, PDA, PMV Yau et al. [34] China 2016 RCS 513 BW < 1500 g or 18.5 GA, BW, IVH GA < 32 w Owen et al. [35] United States 2017 RCS 457 BW < 1250 g or 47.5 GA, BW, maternal Mg GA < 30 w prophylaxis, need of any surgery Ahuja et al. [36] India 2018 PCS 325 BW < 1900, GA < 32.6 BW 36 w Bas et al. [37] Turkey 2018 PCS 6115 BW < 1500 g, or 27.0 GA, BW, days on GA < 32 w, or oxygen, sepsis, BT, unstable clinical relative weight gain course ROP retinopathy of prematurity, MRCT multicenter randomized clinical trial, PCS prospective cohort study, RCS retrospective cohort study, g grams, w weeks, NR not reported, GA gestational age, BW birth weight, PMV prolongued mechanical ventilation, IVH intraventricular hemorrhage, BT blood transfusions, NEC necrotizing enterocolitis; PDA persistent ductus arteriosus, Mg magnesium Freitas et al. Int J Retin Vitr (2018) 4:20 Page 7 of 8 and type 1 prethreshold ROP. This observation suggests BW, low GA, and IVH. Our results revealed that impaired that pulmonary diseases may be used as markers for the lung function as shown by the occurrence of pneumonia, need of larger amount of supplemental oxygen, which is hyaline membrane disease, or bronchopulmonary dys- known to be essential in the pathogenesis of ROP [28]. In plasia, is an important risk factor for the development addition, pulmonary diseases are also possibly associated of ROP and a determinant element of increased risk of with fluctuations in oxygen concentration and episodes of developing type 1 prethreshold ROP. This stage of ROP intermittent hypoxia that are also related to a greater risk of maintains the greatest interest, because it establishes developing ROP [29]. the need of therapeutic intervention. To the best of our The logistic regression model revealed that pulmonary knowledge, this is the first study reporting the associa - diseases and BW < 1000 g are the main risk factors for the tion between pulmonary diseases and type 1 prethresh- development of type 1 prethreshold ROP. BW as a continu- old ROP. Further prospective studies assessing these ous variable and the presence of pulmonary diseases were variables are required in order to evaluate the magnitude used to calculate the logistic probability of development of of the cause-effect relationship between pulmonary dis - type 1 prethreshold ROP. Figure 1 shows that the lower the eases and severe ROP. BW, the greater the probability of type 1 prethreshold ROP. This figure also illustrates that the association between low Abbreviations BW and pulmonary diseases is a determining factor in the ROP: retinopathy of prematurity; BW: birth weight; CPAP: continuous positive increase of this probability. This figure demonstrates that, airway pressure; ELBW: extremely low birth weight; ETROP: early treatment for retinopathy of prematurity; GA: gestational age; IVH: intraventricular hemor- in patients without pulmonary diseases, progressively rhage; NB: newborn; NICU: neonatal intensive care unit. lower BW lead to an increase in the risk of developing type 1 prethreshold ROP, however, in lower percentage when Authors’ contributions AMF conceptualized and designed the study, collected data, designed the compared to the group with pulmonary diseases. database, carried out the statistical analyses and interpretation, drafted the The aim of this study was not to assess the outcome of initial manuscript, and critically reviewed and revised the manuscript. RM patients with type 1 prethreshold disease, but it is worth and ELR supervised the study and critically reviewed the manuscript. MRT collected data and critically reviewed and revised the manuscript. All authors mentioning that they were all treated with diode laser pho- read and approved the final manuscript. tocoagulation and showed complete regression of ROP. The limitations of the present study include its retrospec - Author details Universidade Federal de Ciências Da Saúde de Porto Alegre (UFCSPA), Rua tive nature limiting the control over the quality of meas- Sarmento Leite, 245, Porto Alegre, RS 90050-170, Brazil. Royal Liverpool urements. It should also be taken into account that we University Hospital, Prescot St, Liverpool L7 8XP, UK. have included neonates born over a 10-year period, when Acknowledgements changes in neonatal care may have been implemented. We would like to thank Paulo Henrique Englert, MD; Luciana Emilia Reginato, Nevertheless, the advantages of the study, which ensured MD; Betina Wächter, MD; Debora Cestari, MD. its clinical importance, include a robust sample size, the Competing interests assessment of the disease under study by a single trained The authors declare that they have no competing interests. examiner, and the availability of intensive care resources at a tertiary hospital serving a large population of a metro- Availability of data and materials The datasets used and/or analysed during the current study are available from politan area. Furthermore, a detailed statistical analysis was the corresponding author on reasonable request. determinant to reduce study bias. Although a variety of instruments have been available to Consent for publication Not applicable. image premature neonates, we did not have access to imag- ing devices during the course of the study. Objective docu- Ethics approval and consent to participate mentation of the disease requires a trained imager with The project was approved by the Research Ethics Committee of Santa Casa de Misericórdia de Porto Alegre (Certificate of Ethical Appreciation no. skills to obtain images of satisfactory quality. Expert grad- 45,477,615.4.0000.5335). The ethics committee does not require informed con- ing is accurate and used to compare with imaging graders sent from patients in retrospective cohort studies. The authors have signed a in several studies [30]. confidentiality agreement regarding collected data. Funding Conclusion The authors have no financial relationships relevant to this article to disclose. Although the incidence of ROP in our study was at inter- mediate levels compared to Brazilian studies with anal- Publisher’s Note ogous design, our mean incidence was very similar to Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. worldwide results, as the Vermont Oxford Network data- base. Our study contributed to the analysis of risk factors Received: 5 March 2018 Accepted: 26 May 2018 associated with ROP, supporting the importance of low Freitas et al. Int J Retin Vitr (2018) 4:20 Page 8 of 8 References 20. Kim SJ, Port AD, Swan R, Campbell JP, Chan RVP, Chiang MF. Retinopathy 1. Beharry KD, Valencia GB, Lazzaro DR, Aranda JV. Pharmacologic interven- of prematurity: a review of risk factors and their clinical significance. Surv tions for the prevention and treatment of retinopathy of prematurity. Ophthalmol. 2018. https ://doi.org/10.1016/j.survo phtha l.2018.04.002. Semin Perinatol. 2016;40:189–202. 21. 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Journal

International Journal of Retina and VitreousSpringer Journals

Published: May 31, 2018

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